MHC class I genes are affected by a variety of exogenous stimuli which can either increase or decrease levels of expression. Although agents such as TNF and interferon are well known modulators of class I genes, many other factors also alter expression. We have observed that the thyroid stimulating hormone (TSH) specifically reduces transcription of endogenous class I genes in cultured thyrocytes. Thyrocytes normally express MHC class I, as does a rat thyrocyte cell line, FRTL-5. TSH treatment of FRTL-5 cells decreases transcription of both TSH receptor and class I genes. This downregulation is cAMP mediated and TSH receptor dependent. The TSH responsive element has been located within 135 bp upstream of the class I promoter, to a region which contains a CRE-like element. Analysis of cell extracts from normal and TSH-treated thyrocytes reveals TSH-mediated differences in the factors binding to the CRE. Other agents are capable of modulating class I expression. Among them, insulin, hydrocortisone, and serum act as negative regulators of class 1. Their sites of action are distinct from those of TSH. The DNA element responsive to serum maps to a constitutive negative regulatory element, RE-105. Analysis of RE-105 does not reveal a recognizable serum response element (SRE). However, an APl-like binding site occurs within this region. Indeed, c-jun has been shown to be a negative regulator of class I gene expression.